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PCSC Response to Androgen Deprivation & Other Therapeutics

Mounting evidence suggests that CSCs may be more resistant to anti-cancer therapeutics, as shown in leukemic and multiple myeloma stem cells. CD133+ CSCs increase following radiation and contribute to glioblastoma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The CD44+CD24lo/- breast CSCs are enriched in breast cancer patients who have received adjuvant chemotherapy and more resistant to some chemotherapeutic drugs. In mouse models of mammary tumors, CSCs have also been shown to be refractory to cisplatin treatment. Furthermore, chemoresistant colon cancer cells display CSC phenotypes and CD133+ hepatic CSCs are chemoresistant due to preferential activation of the Akt pathway. These newly emerged findings highlight potential involvement of CSCs in therapy resistance and in recurrence of the disease. For a general review of CSCs and therapy resistance, see Yan et al., 2009.

Our recent studies have corroborated our earlier ‘hunches’ that PCSCs are more resistant to ADT such as androgen deprivation and bicalutamide. Importantly, PCSCs are also refractory to chemotherapeutic drugs and pro-oxidants. These new findings are consistent with our hypothesis that prostate CSCs might be the cells that survive ADT and give rise to castration-resistant recurrent tumors. On the other hand, we have also observed that some drug-tolerant (prostate) cancer cells, surprisingly, are long-lived and possess significantly reduced tumorigenicity. These latter observations are consistent with recent reports on drug-tolerant lung cancer cells and reinforce the concept that CSCs may represent a dynamic state rather than a fixed static population and that some drug-resistant PCa cells may well be dormant and display reduced tumorigenicity at certain time point.

Given these exciting new findings from our studies, what molecules might be involved in regulating PCSC immortality (self-renewal)?


© 2014 The University of Texas MD Anderson Cancer Center